WO2006089113A2 - Marqueurs biologiques permettant de predire l'efficacite d'un traitement de fibrose hepatique - Google Patents

Marqueurs biologiques permettant de predire l'efficacite d'un traitement de fibrose hepatique Download PDF

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WO2006089113A2
WO2006089113A2 PCT/US2006/005638 US2006005638W WO2006089113A2 WO 2006089113 A2 WO2006089113 A2 WO 2006089113A2 US 2006005638 W US2006005638 W US 2006005638W WO 2006089113 A2 WO2006089113 A2 WO 2006089113A2
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interferon
treatment
itac
levels
ifn
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Larry Blatt
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Intermune, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
    • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Definitions

  • the present invention is in the field of clinical medicine and relates to methods for predicting or determining the efficacy of certain medical treatments, especially treatments for liver fibrosis.
  • the methods of the invention include measuring interferon-induced ligands prior to initiating treatment and at some time following the initiation of treatment to predict the clinical outcome of the treatment.
  • the invention thus has applications to the field of medicine.
  • Liver fibrosis is the abnormal accumulation of fibrous scar tissue in the liver. It is a dynamic process resulting from reiterative tissue injury and the chronic activation of tissue repair mechanisms. Fibrosis may be a step in the progression from hepatic inflammation, to fibrosis, to cirrhosis, and even to hepatocellular carcinoma. However, the term fibrosis is often used interchangeably with cirrhosis.
  • Liver fibrosis has a number of known causes, including but not limited to, parasitic infection, trauma, and autoimmune diseases.
  • Parasitic infection includes both extracellular parasites (e.g., Shistosomes, Clonochis, Fasciola, Opistorchis, and Dicrocoelium), and intracellular parasites (e.g., viruses, fungi, and even some bacteria).
  • Viruses known to cause liver fibrosis include, but are not limited to, hepatitis A, B, and C, hepatitis delta and epsilon virus, and other viruses that are trophic for hepatic cells.
  • HCV hepatitis C virus
  • a primary mode of transmission for HCV is intravenous (IV) recreational drug use.
  • IV intravenous
  • the sharing of injection equipment was commonplace 25-30 years ago, before IV drug users were aware of the risk of disease transmission and clean needle programs were available. Accordingly, large numbers of individuals now infected with HCV (and either asymptomatic or suffering only mild, non-descript symptoms) are expected to enter the late stages of HCV infection, sparking fears that they will inundate national healthcare systems with liver cirrhosis cases (Foster, supra).
  • Treatment of hepatitis resulting from autoimmune disease is generally limited to immunosuppression with corticosteroids.
  • Treatment of viral hepatitis i.e., caused by hepatitis B and C virus (HBV and HCV, respectively), usually comprises administration of recombinant interferon alpha (IFN- ⁇ ), optionally with the nucleoside analog ribavirin.
  • IFN- ⁇ interferon alpha
  • IFN- ⁇ treatments involving IFN- ⁇ are only 25-50% effective and not well- tolerated by patients. Most complain of flu-like symptoms, including high fever, malaise, fatigue, nausea, and vomiting. Suicidal depression has even been observed in a small number of patients. Clinically, patients treated with IFN- ⁇ present with such side-effects as thrombocytopenia, leukopenia, and hemolytic anemia. The addition of ribavirin to the treatment regimen only increases the incidence and severity of side effects. In view of the side effects and the low cure rate, up to 20% of patients terminate treatment, opting to submit to the natural course of the disease, or await more tolerable treatments methods (Foster, supra).
  • Chemokines are a subgroup of cytokines that are important in immune and inflammatory response. Chemokines are divided based on the arrangement of conserved cysteine motifs. For example, CC chemokines ( ⁇ -chemokines) comprise adjacent cysteine residues; CXC chemokines ( ⁇ -chemokines) comprise cysteine residues separated by a single, additional residue; and CX3C chemokines comprise cysteine residues separated by three additional residues ⁇ see, e.g., Cole et al. (1998) J Exp. Med. 187:2009-2021.
  • the CXC chemokines are further divided into ELR and non-ELR chemokines, depending on the presence or absence of an additional Glu-Leu-Arg ⁇ i.e., ELR) tripeptide sequence adjacent to the CXC motif.
  • ELR CXCs include interleukin-8 (IL-8), epithelial-derived neutrophil-activating protein (ENA), several growth-related proteins ⁇ e.g., GRO- ⁇ , ⁇ , ⁇ ), and neutrophil-activating protein (NAP).
  • Non-ELR CXC chemokines include interferon- ⁇ (IFN- ⁇ )-inducible 10-kDa protein (IP- 10), IFN- ⁇ -induced monokine (MIG), IFN- inducible T-cell chemoattractant (iTAC), and stromal cell-derived factor (SDF) (Cole et al.; Sauty et al. ⁇ 1999) J. Immunol. 162:3549-58.
  • IFN- ⁇ interferon- ⁇
  • MIG IFN- ⁇ -induced monokine
  • iTAC IFN- inducible T-cell chemoattractant
  • SDF stromal cell-derived factor
  • IP- 10, MIG, and iTAC are potent chemoattractants for activated T-cells but not resting T-cells, B-cells or natural killer (NK) cells. Their expression appears to be upregulated in ThI -associated disorders, in response to which IFN- ⁇ is expressed. IP-10, MIG, and iTAC expression is primarily associated with activated endothelial cells and IFN- ⁇ - activated macrophages.
  • IP-10 is IFN- ⁇ -induced in monocytes, fibroblasts, astrocytes, keratinocytes, neutrophils, and endothelial cells, with expression being associated with, e.g., ulcerative colitis, atherosclerosis, sarcoidosis, tuberculoid leprosy, psoriasis, and viral meningitis (Sauty et al.; Qin et al.).
  • MIG is IFN- ⁇ -mduced in peripheral blood mononuclear cells (PBMCs), fibroblasts, keratinocytes, endothelial cells, and PMA-stimulated monocytes. MIG expression is also associated with psoriasis. iTAC is expressed by activated monocytes and astrocytes.
  • the invention provides methods and kits for predicting the therapeutic efficacy of an interferon-based or related method for treating liver fibrosis.
  • the methods include predicting the therapeutic efficacy of the interferon-based treatment based on the change in the level of an interferon-induced ligand in the patient in response to the administration of an interferon to the patient.
  • the methods include determining the change in the level of an interferon-induced ligand in the patient in response to the administration of an interferon to the patient; and predicting the therapeutic efficacy of the interferon-based treatment based on the change in the level of the interferon-induced ligand.
  • the methods include determining the patient's level of an interferon- induced ligand prior to administration of an interferon to the patient; determining the patient's level of an interferon-induced ligand following commencement of the interferon treatment; and predicting the therapeutic efficacy of the interferon-based treatment based on the change in the level of the interferon-induced ligand.
  • the methods include measuring the patient's level of an interferon-induced ligand, prior to administration of an interferon to the patient; administering a therapeutic amount of an interferon to the patient; measuring the patient's level of the interferon-induced ligand; and determining the change in the level of the interferon-induced ligand in response to the administration of the interferon.
  • One or more interferon-induced ligand may be measured and used according to the method, some of which are identified, herein. Examples of such ligands are iTAC, MIG, and IP-IO.
  • the invention also provides a method for assessing the efficacy of an interferon- based treatment for a liver-related disorder in a patient.
  • the method includes assessing the efficacy of interferon treatment based on the relative increase in the levels of the at least one interferon-induced ligand in the patient.
  • the method includes measuring a patient's levels of at least one interferon-induced ligand prior to interferon treatment; measuring the patient's levels of the at least one interferon-induced ligand following interferon treatment; and assessing the efficacy of the interferon treatment based on the relative change in the levels of the at least one interferon-induced ligand.
  • the method includes determining the relative increase in the levels of at least one interferon-induced ligand in a patient following administration of a composition comprising interferon to the patient; comparing the relative increase to a cut-off value; and assessing the efficacy of interferon treatment based on the relative increase in the levels of the at least one interferon-induced ligand compared to the cut-off value.
  • the method includes measuring a patient's levels of at least one interferon-induced ligand prior to interferon treatment; measuring the patient's levels of the at least one interferon-induced ligand prior following interferon treatment; comparing the relative increase or increases to one or a set of clinically or otherwise determined cut-off or threshold values for each interferon-induced ligand or combinations, thereof; and assessing the efficacy of the interferon treatment based on the relative increase in the levels of the at least one interferon-induced ligand in view of the cut-off value or values.
  • the method includes measuring a patient's levels of at least one interferon-induced ligand, prior to treatment and at least once several weeks following treatment; administering to the patient a therapeutic amount of a composition comprising interferon; determining the relative increase in the levels of the at least one interferon-induced ligand following the administering of the interferon-comprising composition; comparing the relative increase or increases to one or a set of clinically or otherwise determined cut-off or threshold values for each interferon- induced ligand or combinations, thereof; and assessing the efficacy of the interferon treatment based on the relative increase in the levels of the at least one interferon-induced ligand in view of the cut-off value or values.
  • the invention further provides a method for predicting the clinical outcome of a treatment involving the administration of IFN- ⁇ to a patient with chronic hepatitis.
  • the method involves measuring the relative change in the serum levels of at least one biomarker, comparing the relative change to cut-off values; and predicting the clinical outcome of the treatment using the information obtained from the comparison and the conclusions or predictions drawn therefrom.
  • Such patients may have or risk developing a liver disorder such as liver fibrosis.
  • the invention further provides a method for modifying or adjusting a treatment involving the administration of IFN- ⁇ , based on the levels of biomarkers in the patient, the method comprising measuring a patient's serum levels of at least one biomarker prior to treatment and at least once following initiation of treatment, determining the relative change in the levels of at least one biomarker, comparing the relative change to cut-off values, and adjusting the amount of IFN- ⁇ administered to the patient and/or the frequency of administration of IFN- ⁇ , such that the relative change in one of more biomarkers, with respect to the levels prior to treatment, conform to those levels found in patients that have favorable clinical outcomes following IFN- ⁇ treatment.
  • the levels of biomarkers are periodically determined, and the EFN- ⁇ dosage or frequency of administration is adjusted such that a patient receives no more or less IFN- ⁇ that is necessary to keep relative biomarker levels at or near the cut-off values known to be indicative of a favorable clinical outcome.
  • kits which include parts for practicing the methods described herein and that will be apparent from the examples provided herein.
  • the kit of parts, or kits may include reagents for collecting and or measuring serum levels of one or more interferon-induced ligand. Such reagents may include antibodies.
  • the kits may further include equipment for collecting and/or processing biological samples.
  • the kits are also likely to contain instructions for use, cut-off values and/or instructions for their determination, and instructions for interpreting the data obtained from the use of the kits.
  • the invention further provides computer programs and/or algorithms for calculating the relative increase in interferon-induced ligands, determining whether such increases are above or below a threshold level, and/or recommending modifications to a treatment regiment to improve a patient's response to an interferon-based therapy.
  • the computer programs or algorithms may be provided along with necessary hardware, e.g., in the form of a kit or apparatus, which may also accept biological samples and measure the relative levels of intereferon-induced ligands present therein.
  • Figure 1 is a graph showing the change in patient serum iTAC levels, before treatment or at 24 weeks following treatment with IFN- ⁇ (or placebo).
  • IFN-100 100 ⁇ g IFN ⁇ /week
  • IFN-200 200 ⁇ g IFN ⁇ /week.
  • Figure 2 is a graph showing the distribution of patients with >45% increase in serum iTAC levels following treatment with interferon (100 ⁇ g/week or 200 ⁇ g/week) or placebo. Changes in liver histology are based on Ishak scores.
  • Figure 3 is a graph showing changes in liver histology in populations of patients with >45% iTAC or ⁇ 45% iTAC induction following treatment. Changes in liver histology are based on Ishak scores.
  • Figure 4 is a graph showing the change in patient serum MIG levels, before and after treatment with interferon or placebo.
  • IFN-100 100 ⁇ g IFN ⁇ /week
  • IFN-200 200 ⁇ g IFN ⁇ /week.
  • Figure 5 is a graph showing the change in patient serum IP-10 levels, before and after treatment with interferon or placebo.
  • IFN-100 100 ⁇ g IFN ⁇ /week
  • IFN-200 200 ⁇ g
  • Figure 6 shows a logistic regression analysis examining iTAC induction and liver histology outcome.
  • Figure 7 shows a logistic regression analysis examining co-variant CXCR3 ligands by liver histology outcome.
  • Figure 8 is a table showing the percent change in serum levels of iTAC, MIG, and IP-IO levels, from baseline to week 24, arranged by treatment group.
  • Figure 9 is a table showing a logistic regression model for predictors of a stable or improving Ishak fibrosis scores at the end of the treatment study, relative to baseline.
  • Figure 10 is a table showing the distribution of patients with >59.33% iTAC induction, arranged by treatment group.
  • Figure 11 is a table showing the correlation between Ishak fibrosis scores worsening at the end of the treatment study, relative to baseline, and the percent change in iTAC at week 24, relative to baseline.
  • Figure 12 is a table showing a logistic regression analysis correlating predictors of a stable or improving Ishak Fibrosis Scores at end of the treatment study, relative to baseline and arranged by treatment group, with observations weighted by percent change in iTAC at Week 24, relative to baseline.
  • the invention provides materials and methods for predicting the efficacy of liver fibrosis treatment using biological markers that have been determined to be substantially reliable predictors of liver histology.
  • the markers are present in biological samples obtained from the patient.
  • the methods and materials provided by the invention enable the assessment of a patient's treatment progress, thereby delaying or obviating the need for invasive, dangerous liver biopsy and histology to monitor the efficacy of treatment and limiting the suffering of a patient undergoing ineffective therapy.
  • the methods and materials of the invention are used to evaluate patients having liver fibrotic diseases, and the biological markers (biomarkers) are CXCR3 ligands that are induced by interferon- ⁇ (IFN- ⁇ ). Changes in the levels of these ligands can be detected in the blood following the initiation of an IFN-7-based treatment.
  • the biological markers are CXCR3 ligands that are induced by interferon- ⁇ (IFN- ⁇ ). Changes in the levels of these ligands can be detected in the blood following the initiation of an IFN-7-based treatment.
  • the relative increase or decrease of the ligands is indicative of treatment efficacy.
  • the relative change in serum levels is compared to cut-off (or threshold) values as described herein.
  • the studies that gave rise to the methods of the invention involved the treatment of a population of patients with cirrhotic, chronic hepatitis C, with IFN- ⁇ .
  • the patients were divided into three groups: (1) a group that received a placebo (i.e., no IFN- ⁇ ), (2) a group that received 100 ⁇ g IFN- ⁇ /week, and (3) a group that received 200 ⁇ g IFN- ⁇ /week.
  • Serum samples were collected from patients prior to treatment (designated baseline samples) and at week-24 following the initiation of treatment.
  • the liver histology of these patients was examined at the conclusion of the study, and quantified using Ishak scores (Ishak et al. (1995) Histological grading and staging of chronic hepatitis. J Hepatol. 22:696-99), which are well-known in the art of diagnosing and treating liver diseases.
  • CXC cytokines were measured in the collected serum samples.
  • the levels of the CXCR3 ligands, iTAC, MIG-9, and IP-10 were measured by ELISA assay, using commercially available antibody kits (R&D Systems, Minneapolis, MN, USA).
  • Statistical analyses of the levels of these CXCR3 ligands were performed to determine whether such ligands were useful biological markers (biomarkers) for the clinical efficacy of IFN- ⁇ treatment, as ultimately determined by improved liver histology.
  • Figure 2 is a graph showing the distribution of patients with a greater than 45% increase in serum iTAC levels following treatment with interferon or placebo. The results show that increasing iTAC levels are clearly associated with IFN- ⁇ treatment, and that patients receiving a larger dose of IFN- ⁇ show a greater increase in iTAC levels. Less than 10% of patients receiving placebo showed an increase in iTAC levels. .. [0041] Furthermore, patients with a >45% increase in iTAC levels (also referred to herein as iTAC induction) were less likely to show worsening of liver histology (based on Ishak scores) than patients with a ⁇ 45% iTAC induction following treatment (Figure 3).
  • iTAC induction also referred to herein as iTAC induction
  • the IFN-100 group showed a mean increase in serum ' MIG levels of about 50%, at 24 weeks following the initiation of treatment compare to baseline levels.
  • the EFN-200 group showed a 110% increase in MIG levels.
  • the placebo group showed essentially no increase (8%).
  • the IFN-100 group showed a mean increase in serum IP-10 levels of about 50%, at 24 weeks following the initiation of treatment compare to baseline levels.
  • the IFN-200 group showed a 68% increase and placebo group showed essentially no increase (5%).
  • ROC receiver operating characteristic
  • biomarker induction values >200% are likely to be highly predictive of a successful clinical outcome, notwithstanding the cut-off values.
  • Figures 1-3 show that some patients show a 500%, or greater, increase in iTAC, MIG, or IP-10, following treatment with IFN- ⁇ . These high levels of biomarker inductions are simply not observed in patients receiving placebo and are predictive of clinical efficacy. While iTAC appears to be the most reliable biomarker examined in the study, MIG and IP-10 expression also clearly correlate with IFN- ⁇ treatment.
  • the methods of the invention can be used to predict the clinical outcome of a treatment comprising the administration of IFN- ⁇ to a patient suffering from liver disease.
  • the disease it liver fibrosis, a condition associated with the accumulation of scar tissue in the liver.
  • liver fibrosis is a stage in the progression of various inflammatory hepatic disorders, that lead to fibrosis, cirrhosis and even to carcinoma.
  • Liver fibrosis and cirrhosis are used interchangeably, herein, and the methods are not limited by arbitrarily definitions used by clinicians to identify different stages of liver degeneration.
  • liver fibrosis scoring systems for measuring liver fibrosis are known in the art, including the Ishak system (used herein), the Scheur system, the Knodell system, and the Metavir system.
  • the methods of the invention may be used with any fibrosis scoring system and is by no means limited to use with only the Ishak system.
  • the treatment comprising the administration of IFN- ⁇ may further comprise other interferons (including but not limited to EFN- ⁇ , ⁇ , ⁇ , and ⁇ ), specific inhibitors of HCV polypeptides (including but not limited to NS3 and NS5), stress-activated protein kinase (SAPK) inhibitors, pirfenidone and perfinidone analogs, tumor necrosis factor (TNF)- ⁇ antagonists, TNF receptor polypeptides or polypeptides that mimic the TNF receptor, antibodies that inhibit TNF- ⁇ , thymosin- ⁇ , ribavirin, leovirin, viramidine, nucleoside analogs and other antiviral agents.
  • interferons including but not limited to EFN- ⁇ , ⁇ , ⁇ , and ⁇
  • specific inhibitors of HCV polypeptides including but not limited to NS3 and NS5
  • SAPK stress-activated protein kinase
  • pirfenidone and perfinidone analogs including
  • the treatment may also comprise anti-inflammatory agents, antiphychotic or antineurotic drugs, drugs that reduce gastrointestinal discomfort, histamine type 2 receptor antagonists, antacids, antiemetics, antidiarreal agents, hematopoietic agents, and other drugs that have antiviral activity, alleviate the symptoms of viral infection, or alleviate the side-effects of treatment.
  • the level of interferon-induced ligands in a biological sample from a patient is determined prior to initiation of therapy (the initial measurement) and at least one time following the initiation of therapy ⁇ i.e., the second measurement).
  • the time between the initial and second measurements may be 1 day to about 48 weeks or more ⁇ e.g., from about 1 day to about 1 week, from about 1 week to about 2 weeks, from about 2 weeks to about 4 weeks, from about 4 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 12 weeks to about 16 weeks, from about 16 weeks to about 24 weeks, from about 24 weeks to about 48 weeks, or more) after the treatment regimen has been initiated, hi a preferred embodiment of the invention, the time interval is about 24 weeks.
  • additional measurements ⁇ i.e., a third, fourth, fifth, etc. measurement) may be taken at similar time intervals following the second measurement.
  • the methods will also allow clinicians and patients to monitor the efficacy of treatment over a prolonged period of time, for example, to ensure that a once-effective treatment has not become ineffective or that liver fibrosis has unexpectedly accelerated late in treatment. Such methods may be particularly useful for monitoring the efficacy of liver fibrosis treatment in long-term care patients, patients with liver transplants, or patients having or at risk for autoimmune or immune deficiency disorders, diseases, or conditions.
  • the biomarkers are present in a biological sample obtained from the patient.
  • Biological samples include but are not limited to blood and other liquid samples of biological origin, solid tissue samples, such as a biopsy specimen or tissue cultures or cells derived therefrom and the progeny thereof.
  • the samples may have been manipulated in after procurement, such as by treatment with one or more reagents, solubilization, or enrichment for certain components.
  • Suitable samples for use with the invention include blood, serum, plasma, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, urine, cerebrospinal fluid, saliva, sputum, tears, perspiration, mucus, cell culture medium, cell supernatant, and cell or tissue extracts.
  • Interferons for use in the invention may be naturally occurring, recombinant, or synthetic. Such interferons may be truncated, substituted, or modified.
  • the interferons are pegylated at one or more amino acid residues.
  • the peg moieties may be linear or branched, attached directly or via a linker, and attached at the N- terminus, C-terminus, specific internal amino acid residues, or otherwise attached to one or more of the above-described interferons.
  • a relative increase in the levels of biomarkers is indicative of a successful clinical outcome for the treatment, i.e., the reduction in liver fibrosis.
  • the relative increase in biomarker levels is compared to cut-off values known to reliable in predicting clinical outcome.
  • the iTAC cut-off values described herein range from about 45% to about 59%. However, other cut-off values can be obtained, e.g., for different patient populations, using the experimental and statistical methods disclosed herein. Such cutoff values may be less than 45%, but at least, for example, 40%, 35%, 30%, 25%, or 20%.
  • cut-off values may also be greater than about 59%, for example, at least about 65%, 75%, 85%, 95%, or more. In preferred embodiments of the invention, the cut-off values are likely to be between about 45% and 65%, for example, 50%, 55%, or 60%.
  • a relative decrease in the biomarker levels is generally indicative of treatment failure or lack of response by the patient, even without the use of cut-off or threshold values.
  • IFN- ⁇ Monitoring the relative levels of biomarkers throughout, or during at least part of, IFN- ⁇ treatment will also allows patients and clinicians to adjust an IFN- ⁇ treatment regimen for optimal therapeutic benefit. For example, patients with relative increases in biomarkers that are below the cut-off values can be given increased amounts (dosages) of IFN- ⁇ , more frequent administrations of IFN- ⁇ , different forms of IFN- ⁇ , or other pharmaceutical compositions to increase the efficacy of the IFN- ⁇ treatment, including but not limited to those identified above and/or below, to increase their biomarker levels. It may also be desirable to give these patients other pharmacological composition, such as those discussed above and/or below, to reduce the side-effects associated with increased dosages of IFN- ⁇ .
  • IFN- ⁇ administration in patients with high relative levels of biomarkers, such that the patient maintains relative biomarker levels that are at or above the cut-off values, but the patient does not receive more IFN- ⁇ than is necessary to achieve a therapeutic effect.
  • side effects from IFN- ⁇ treatment are minimized without sacrificing therapeutic efficacy.
  • the levels of biomarkers are measured in biological samples obtained from the patient.
  • the biological sample is blood or serum, in which case obtaining the samples from a patient is relatively simple and non-invasive procedure.
  • Methods of obtaining blood are well-known in the art are not part of the invention.
  • numerous methods for detecting and quantifying polypeptides, including the instant biomarkers are known. Such methods include but are not limited to antibody-based methods. The particular methods of detecting and quantifying the biomarkers are not important to the invention.
  • the methods of the invention may be combined with other methods for predicting the efficacy of treatment for liver fibrosis.
  • the methods may be used to monitor the clinical progress or predict the clinical outcome of other diseases associated with CXCR3 ligand expression.
  • ThI-associated disorders include but are not limited to delayed-type hypersensitivity, insulin- dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, contact hypersensitivity, and inflammatory bowel disease.
  • ThI- mediated disorders include but are not limited to delayed-type hypersensitivity, insulin- dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, contact hypersensitivity, and inflammatory bowel disease.
  • biomarkers and statistical methods described herein one skilled in the art can determine appropriate cut-off values for changes in the serum levels of these biomarkers that correspond to particular disease states in different ThI- mediated disorders.
  • Serum levels of the ligands can then be measured, compared to the cutoff values, and used to monitor disorders, or predict the clinical outcome of disorders, in patients with ThI -mediated disorders, including patients receiving treatment for such disorders.
  • serum IP- 10 levels may be particularly important in monitoring/predicting the course of diseases such as ulcerative colitis, atherosclerosis, sarcoidosis, tuberculoid leprosy, psoriasis, and viral meningitis.
  • Serum MIG levels may be particularly important in monitoring/predicting the course of psoriasis.
  • the levels of biomarkers are also of value in distinguishing between different forms of B-cell lymphomas.
  • MIG is expressed in some B-cell lymphomas, including B CLL/SLL (Jones et al. (2000) Neoplasia 95:627-632).
  • the percent change in the level of interferon-inducible gene product can be calculated manually, e.g., by a human, or completely or partially performed by a computer program or algorithm along with necessary hardware, such as input, memory, processing, display, and output devices.
  • the computer program or algorithm can calculate the percent increase in the level of interferon-inducible gene product, determine whether the increase is above or below a threshold, assess the efficacy of the treatment regimen, and propose modifications to the therapy intended to increase the likelihood that a patient will respond favorably to treatment.
  • the instant invention further provides an apparatus for determining the levels of interferon-induced ligands in a biological sample.
  • the apparatus is capable of measuring the levels of one or more interferon-induced ligands in a biological sample, storing such data, and ultimately using such data in the analyses described, upon.
  • the apparatus is portable.
  • the apparatus is suitable for use in a physicians office, providing the physician with the means for quickly determining the efficacy of an interferon- based treatment without sending biological sample to a clinical laboratory.
  • part or all of the data collection and analysis may be performed by a clinical laboratory.
  • the above-described computer programs and/or apparatus are likely to be provided to physicians or clinical laboratories with appropriate instructions and reagents, including antibodies.
  • Serum samples were collected from test subjects/patients prior to treatment (baseline samples) and at week 24 following initiation of therapy.
  • the serum levels expressed as mg/dL, of each of the three CXCR3 ligands, iTAC, MIG-9, and IP-10, were measured by ELISA assay, using antibodies specific for each ligand.
  • the ANOVA test was used to determine statistical significance with a post hoc t- test to determine pair-wise differences.
  • EXAMPLE 2 Percent change in iTac levels following IFN- ⁇ therapy in cirrhotic chronic hepatitis C patients
  • Example 1 The data obtained from Example 1 were used to calculate the relative change in serum levels of iTac at week 24 following treatment, relative to the baseline levels. The results are shown below:
  • EXAMPLE 3 Percent change in MIG levels following IFN- ⁇ therapy in cirrhotic chronic hepatitis C patients
  • Example 2 The data obtained from Example 1 were used to calculate the relative change in serum levels of MIG at week 24 following treatment, relative to the baseline levels. The results are shown below:
  • EXAMPLE 4 Percent change in IP-10 levels following IFN- ⁇ therapy in cirrhotic chronic hepatitis C patients
  • Example 2 The data obtained from Example 1 were used to calculate the relative change in serum levels of IP-10 at week 24 following treatment, relative to the baseline levels. The results are shown below:
  • Table 1 shows the percent change, from baseline to week 24, in the serum levels of iTAC, MIG, and IP-10, organized by treatment group, i.e., patients receiving placebo, 100 ⁇ g/week IFN (IFN-100), or 200 ⁇ g/week IFN (IFN-200). The number of patients in each group, average percent change with standard deviations, minimum, maximum, and percentile scores are shown.
  • Receiver operating characteristic (ROC) analyses were performed based on the ability of the "percent iTAC induction," i.e., the percent change in iTAC levels from baseline to week 24, to determine if patients had stable or improving Ishak fibrosis scores from baseline to end of treatment (Figure 10).
  • the optimal cut-off point for percent iTAC induction was determined by maximizing Cohen's kappa using all observed percent iTAC induction values between the 25 th and 75 th percentiles. Patients in each treatment group with percent iTAC induction values at or above the optimal cut-off point were summarized with counts and percentages.

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  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention concerne des procédés permettant de prédire ou de déterminer l'efficacité de certains traitements médicamenteux, en particulier des traitements pour la fibrose hépatique. Les procédés de l'invention consistent à mesurer des ligands induits par un interféron avant le commencement du traitement et à certains moments après le commencement du traitement pour prédire le résultat clinique dudit traitement.
PCT/US2006/005638 2005-02-18 2006-02-17 Marqueurs biologiques permettant de predire l'efficacite d'un traitement de fibrose hepatique WO2006089113A2 (fr)

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US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV
WO2017189978A1 (fr) 2016-04-28 2017-11-02 Emory University Compositions thérapeutiques à base de nucléotides et nucléosides contenant un alcyne et utilisations associées

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WO2011140125A1 (fr) * 2010-05-07 2011-11-10 Hitachi Chemical Co., Ltd. Procédés de caractérisation de la sensibilité d'un hôte à l'interféron par induction ex vivo de marqueurs de réponse à l'interféron
JP6624704B2 (ja) 2015-08-31 2019-12-25 日立化成株式会社 尿路上皮疾患の評価のための分子法

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US5994292A (en) * 1995-05-31 1999-11-30 The United States Of America As Represented By The Department Of Health And Human Services Interferon-inducible protein 10 is a potent inhibitor of angiogenesis

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US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8680106B2 (en) 2011-10-21 2014-03-25 AbbVic Inc. Methods for treating HCV
US8685984B2 (en) 2011-10-21 2014-04-01 Abbvie Inc. Methods for treating HCV
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV
US8969357B2 (en) 2011-10-21 2015-03-03 Abbvie Inc. Methods for treating HCV
US8993578B2 (en) 2011-10-21 2015-03-31 Abbvie Inc. Methods for treating HCV
US9452194B2 (en) 2011-10-21 2016-09-27 Abbvie Inc. Methods for treating HCV
WO2017189978A1 (fr) 2016-04-28 2017-11-02 Emory University Compositions thérapeutiques à base de nucléotides et nucléosides contenant un alcyne et utilisations associées
US11192914B2 (en) 2016-04-28 2021-12-07 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

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